Method of treating androgenic alopecia with 5α-reductase inhibitors

ABSTRACT

The instant invention involves a method of treating and/or reversing androgenic alopecia and promoting hair growth, and methods of treating acne vulgaris, seborrhea, and female hirsutism, by administering to a patient in need of such treatment a 5α-reductase 2 inhibitor such as finasteride, in a dosage amount under 5 mgs/day.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of Ser. No. 08/596,339, filed Feb. 20,1996, now U.S. Pat. No. 5,824,686 which in turn is the national phaseapplication under 35 U.S.C. § 371 of PCT application Serial No.PCT/US94/11507, filed Oct. 11, 1994, which is a continuation-in-part ofU.S. patent application Ser. No. 08/214,905, filed Mar. 17, 1994 andissued as U.S. Pat. No. 5,547,957 and a continuation-in-part of08/138,520, filed Oct. 15, 1993, presently abandoned.

The present invention is concerned with the treatment of androgenicalopecia, including male pattern baldness, with compounds that are5-alpha reductase isozyme 2 inhibitors.

BACKGROUND OF THE INVENTION

Certain undesirable physiological manifestations, such as acne vulgaris,seborrhea, female hirsutism, androgenic alopecia which includes femaleand male pattern baldness, and benign prostatic hyperplasia, are theresult of hyperandrogenic stimulation caused by an excessiveaccumulation of testosterone ("T") or similar androgenic hormones in themetabolic system. Early attempts to provide a chemotherapeutic agent tocounter the undesirable results of hyperandrogenicity resulted in thediscovery of several steroidal antiandrogens having undesirable hormonalactivities of their own. The estrogens, for example, not only counteractthe effect of the androgens but have a feminizing effect as well.Non-steroidal antiandrogens have also been developed, for example,4'-nitro-3'-trifluoromethylisobutyranilide. See Neri, et al.,Endocrinol. 1972, 91 (2). However, these products, though devoid ofhormonal effects, compete with all natural androgens for receptor sites,and hence have a tendency to feminize a male host or the male fetus of afemale host and/or initiate feed-back effects which would causehyperstimulation of the testes.

The principal mediator of androgenic activity in some target organs,e.g. the prostate, is 5α-dihydrotestosterone ("DHT"), formed locally inthe target organ by the action of testosterone-5α-reductase. Inhibitorsof testosterone-5α-reductase will serve to prevent or lessen symptoms ofhyperandrogenic stimulation in these organs. See especially U.S. Pat.No. 4,377,584 assigned to Merck & Co., Inc., issued Mar. 22, 1983. It isnow known that a second 5α-reductase isozyme exists, which interactswith skin tissues, especially in scalp tissues. See, e.g., G. Harris, etal., Proc. Natl. Acad. Sci. USA, Vol. 89, pp. 10787-10791 (November1992). The isozyme that principally interacts in skin tissues isconventionally designated as 5α-reductase 1 (or 5α-reductase type 1),while the isozyme that principally interacts within the prostatictissues is designated as 5α-reductase 2 (or 5α-reductase type 2).

Finasteride (17β-(N-tert-butylcarbamoyl)-4-aza-5α-androst-1-ene-3-one),which is marketed by Merck & Co., Inc. under the tradename PROSCAR®, isan inhibitor of 5α-reductase 2 and is known to be useful for thetreatment of hyperandrogenic conditions. See e.g., U.S. Pat. No.4,760,071. Finasteride is currently marketed in the United States andworldwide for the treatment of benign prostatic hyperplasia.Finasteride's utility in the treatment of androgenic alopecia andprostatic carcinoma is also disclosed in the following documents: EP 0285,382, published Oct. 5, 1988; EP 0 285 383, published Oct. 5, 1988;Canadian Patent no. 1,302,277; and Canadian Patent no. 1,302,276. Thespecific dosages exemplified in the above-noted disclosures varied from5 to 2000 mg per patient per day.

In the treatment of androgenic alopecia, which includes both female andmale pattern baldness, and other hyperandrogenic conditions, it would bedesirable to administer the lowest dosage possible of a pharmaceuticalcompound to a patient and still maintain therapeutic efficacy.Applicants have surprisingly and unexpectedly discovered that a lowdaily dosage of a 5α-reductase 2 inhibitor is particularly useful in thetreatment of androgenic alopecia. Furthermore, a low daily dosage of a5α-reductase 2 inhibitor may also be particularly useful in thetreatment of the hyperandrogenic conditions of acne vulgaris, seborrhea,female hirsutism, and polycystic ovary syndrome.

DETAILED DESCRIPTION OF THE INVENTION

The instant invention involves a method of treating and/or reversingandrogenic alopecia and promoting hair growth, and methods of treatingacne vulgaris, seborrhea, and female hirsutism, which comprisesadministering to a patient in need of such treatment a 5α-reductase 2inhibitor in a dosage amount under 5 mgs/day. In one embodiment of thisinvention, the 5α-reductase 2 inhibitor is administered in a dosageamount of from 0.01 to 3.0 mgs/day. In one class of this embodiment, the5α-reductase 2 inhibitor is administered in a dosage amount of from 0.05to 1.0 mg/day, and in a sub-class of this embodiment, the 5α-reductase 2inhibitor is administered in dosage amounts of about 0.05 to 0.2 mg/day.Illustrating this subclass are dosage amounts of about 0.05, 0.1, 0.15and 0.2 mg/day. Exemplifying the sub-class are dosages of 0.05 and 0.2mg/day. Compounds which are inhibitors of 5α-reductase 2 can bedetermined by employing the assay described below in Example 3.

In a second embodiment of this invention, the method of treatingandrogenic alopecia comprises administration of 5α-reductase 2 inhibitorcompounds which have the structural Formula I ##STR1## or apharmaceutically acceptable salt thereof wherein: R¹ is hydrogen, methylor ethyl;

R² is a hydrocarbon radical selected from straight and branched chainalkyl of from 1-12 carbons or monocyclic aryl optionally containing 1 ormore lower alkyl substituents of from 1-2 carbon atoms and/or 1 or morehalogen (Cl, F or Br) substituents;

R' is hydrogen or methyl;

R" is hydrogen or β-methyl; and

R'" is hydrogen, α-methyl or β-methyl.

In one class of this second embodiment, the 5α-reductase 2 inhibitorcompounds have the structural Formula II ##STR2## or a pharmaceuticallyacceptable salt thereof wherein R¹ is hydrogen, or methyl; and

R³ is branched chain alkyl of from 4-8 carbons.

Representative compounds that may be employed in the present inventioninclude the following:

17β-(N-tert-butylcarbamoyl)-4-aza-5-α-androst-1-en-3-one,

17β-(N-isobutylcarbamoyl)-4-aza-5-α-androst-1-en-3-one,

17β-(N-tert-octylcarbamoyl)4-aza-5-α-androst-1-en-3-one,

17β-(N-octylcarbamoyl)-4-aza-5α-androst-1-en-3-one,

17β-(N-1,1-diethylbutylcarbamoyl)-4-aza-5-α-androst-1-en-3-one,

17β-(N-neopentylcarbamoyl)-4-aza-5-α-androst-1-en-3-one,

17β-(N-tert-amylcarbamoyl-4-aza-5-α-androst-1-en-3-one, and

17β-(N-tert-hexylcarbamoyl)-4-aza-5-α-androst-1-en-3-one;

and the corresponding compounds wherein the 4-nitrogen is substituted ineach of the above named compounds by a methyl or an ethyl radical.

Also included as representative compounds are any of the above indicatedcompounds having the N-branched chain alkyl substituent replaced by amethyl, ethyl, propyl, i-propyl, butyl, phenyl; 2, 3 or 4 tolyl, xylyl,2-bromo or 2-chlorophenyl, 2-6-dichloro, or a 2,6-dibromophenylsubstituent.

The compounds of Formula I and II described above can be synthesizedaccording to procedures well known in the art, and which are described,for example, in U.S. Pat. No. 4,760,071, EP 0 285,382 and EP 0 285 383.The compound finasteride is currently available as a prescriptionpharmaceutical from Merck & Co. Inc. The synthesis of finasteride isdescribed in U.S. Pat. No. 4,760,071. A further synthesis of finasterideis described in Synthetic Communications, 30 (17), p. 2683-2690 (1990).

The present invention has the objective of providing methods of treatingthe hyperandrogenic conditions of androgenic alopecia, including malepattern baldness and female pattern baldness, acne vulgaris, seborrhea,female hirsutism, and polycystic ovary syndrome by systemic, oral,parenteral or topical administration of a 5α-reductase 2 inhibitor in adosage amount under 5 mg/day, and particularly, from about 0.01 mg/dayto 3.0 mg/day, and more particularly 0.05 to 1 mg/day. The invention isfurther illustrated by dosages of about 0.05 to 0.2 mg/day andspecifically dosages of about 0.05, 0.1, 0.15 and 0.2 mg/day.Exemplifying the invention are dosages of 0.05 and 0.2 mg/day. The term"treating androgenic alopecia" is intended to include the arrestingand/or reversing of androgenic alopecia, and the promotion of hairgrowth. Also, a 5α-reductase 2 inhibitor, e.g., finasteride, at a dosageunder 5 mgs/day can be used in combination with a potassium channelopener, such as minoxidil or a pharmaceutically acceptable salt thereof,for the treatment of androgenic alopecia, including male patternbaldness. The 5α-reductase 2 inhibitor and the potassium channel openermay both be applied topically, or each agent can be given via differentadministration routes; for example, the 5α-reductase 2 inhibitor may beadministered orally while the potassium channel opener may beadministered topically.

The present invention also has the objective of providing suitablesystemic, oral, parenteral and topical pharmaceutical formulations foruse in the novel methods of treatment of the present invention. Thecompositions containing 5α-reductase 2 inhibitor compounds as the activeingredient for use in the treatment of the above-noted hyperandrogenicconditions can be administered in a wide variety of therapeutic dosageforms in conventional vehicles for systemic administration. For example,the compounds can be administered in such oral dosage forms as tablets,capsules (each including timed release and sustained releaseformulations), pills, powders, granules, elixirs, tinctures, solutions,suspensions, syrups and emulsions. Likewise, they may also beadministered in intravenous (both bolus and infusion), intraperitoneal,subcutaneous, topical with or without occlusion, or intramuscular form,all using forms well known to those of ordinary skill in thepharmaceutical arts. For oral administration, for example, thecompositions can be provided in the form of scored or unscored tabletscontaining 0.01, 0.05, 0.1, 0.2, 1.0, 2.0 and 3.0 milligrams of theactive ingredient for the symptomatic adjustment of the dosage to thepatient to be treated.

For the treatment of androgenic alopecia including male patternbaldness, acne vulgaris, seborrhea, and female hirsutism, the5α-reductase 2 inhibitor compounds may be administered in apharmaceutical composition comprising the active compound in combinationwith a pharmaceutically acceptable carrier adapted for topicaladministration. Topical pharmaceutical compositions may be, e.g., in theform of a solution, cream, ointment, gel, lotion, shampoo or aerosolformulation adapted for application to the skin. Topical pharmaceuticalcompositions useful in the method of treatment of the present inventionmay include about 0.001% to 0.1% of the active compound in admixturewith a pharmaceutically acceptable carrier.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. The compounds for thepresent invention can be administered in intranasal form via topical useof suitable intranasal vehicles, or via transdermal routes, using thoseforms of transdermal skin patches well known to those of ordinary skillin that art. To be administered in the form of a transdermal deliverysystem, the dosage administration will, of course, be continuous ratherthan intermittent throughout the dosage regimen. Compounds of thepresent invention may also be delivered as a suppository employing basessuch as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils,mixtures of polyethylene glycols of various molecular weights and fattyacid esters of polyethylene glycol.

The dosage regimen utilizing the compounds of the present invention isselected in accordance with a variety of factors including type,species, age, weight, sex and medical condition of the patient; theseverity of the condition to be treated; the route of administration;the renal and hepatic function of the patient; and the particularcompound thereof employed. A physician or veterinarian of ordinary skillcan readily determine and prescribe the effective amount of the drugrequired to prevent, counter, arrest or reverse the progress of thecondition. Optimal precision in achieving concentration of drug withinthe range that yields efficacy without toxicity requires a regimen basedon the kinetics of the drug's availability to target sites. Thisinvolves a consideration of the distribution, equilibrium, andelimination of a drug.

In the methods of the present invention, the 5α-reductase 2 inhibitorcompounds herein described in detail can form the active ingredient, andare typically administered in admixture with suitable pharmaceuticaldiluents, excipients or carriers (collectively referred to herein as"carrier" materials) suitably selected with respect to the intended formof administration, that is, oral tablets, capsules, elixirs, syrups andthe like, and consistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Capsules containing the product of thisinvention can be prepared by mixing an active compound of the presentinvention with lactose and magnesium stearate, calcium stearate, starch,talc, or other carriers, and placing the mixture in gelatin capsule.Tablets may be prepared by mixing the active ingredient withconventional tableting ingredients such as calcium phosphate, lactose,corn starch or magnesium stearate. Moreover, when desired or necessary,suitable binders, lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders includestarch, gelatin, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth orsodium alginate, carboxymethylcellulose, polyethylene glycol, waxes andthe like. Lubricants used in these dosage forms include sodium oleate,sodium stearate, magnesium stearate, sodium benzoate, sodium acetate,sodium chloride and the like. Disintegrators include, withoutlimitation, starch, methyl cellulose, agar, bentonite, xanthan gum andthe like.

The liquid forms in suitably flavored suspending or dispersing agentssuch as the synthetic and natural gums, for example, tragacanth, acacia,methyl-cellulose and the like. Other dispersing agents which may beemployed include glycerin and the like. For parenteral administration,sterile suspensions and solutions are desired. Isotonic preparationswhich generally contain suitable preservatives are employed whenintravenous administration is desired.

Topical preparations containing the active drug component can be admixedwith a variety of carrier materials well known in the art, such as,e.g., alcohols, aloe vera gel, allantoin, glycerine, vitamin A and Eoils, mineral oil, propylene glycol, PPG2 myristyl propionate, and thelike, to form, e.g., alcoholic solutions, topical cleansers, cleansingcreams, skin gels, skin lotions, and shampoos in cream or gelformulations. See, e.g., EP 0 285 382.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

The following example illustrates the present invention and as such arenot to be considered as limiting the invention set forth in the claimsappended hereto.

EXAMPLE 1

Finasteride is known to occur in two distinct polymorphic crystal forms,termed "Form I" and "Form II". Form I is the marketed form offinasteride as a 5 mg tablet (PROSCAR®).

Finasteride Form I can be prepared by dissolving finasteride in glacialacetic acid (ca. 100 mg/ml) and adding water with stirring until theweight % of water equals or exceeds 84%. The resulting solid phase iscollected by filtration and dried under vacuum and at about 50° C. Theresulting Form I is characterized by a differential scanning calorimetry(DSC) curve, at heating rate of 20° C./min and in a closed cup,exhibiting a minor endotherm with a peak temperature of about 232° C.,an extrapolated onset temperature of about 223° C. with an associatedheat of about 11 joules/gm and by a major melting endotherm with a peaktemperature of about of 261° C., an extrapolated onset temperature ofabout 258° C. with an associated heat of about 89 J/gm. The x-ray powderdiffraction pattern is characterized by d-spacings of 6.44, 5.69, 5.36,4.89, 4.55, 4.31, 3.85, 3.59 and 3.14. The FT-IR spectrum shows bands at3431, 3237, 1692, 1666, 1602 and 688 cm-1. The solubilities in water andcyclohexane at 25° C. are 0.05+0.02 and 0.27+0.05 mg/gm respectively. Inaddition, Form I of finasteride can be prepared by recrystallizationfrom dry (H₂ O<1 mg/ml) ethyl acetate and isopropyl acetate. Theisolated solids are dried under vacuum at about 50° C. and have the samephysical characterization data as given above.

EXAMPLE 2

Form II of finasteride can be prepared by dissolving finasteride inglacial acetic acid (ca. 100 mg/ml) and adding water with stirring untilthe weight % of water equals about 75% but not in excess of 80%. Theresulting solid phase is collected by filtration and dried under vacuumand at about 100° C. The resulting Form II is characterized by a DSCcurve, at heating rate of 20° C./min and in a closed cup, exhibiting asingle melting endotherm with a peak temperature of about of 261° C., anextrapolated onset temperature of about 258° C. with an associated heatof about 89 J/gm. The x-ray powder diffraction pattern is characterizedby d-spacings of 14.09, 10.36, 7.92, 7.18, 6.40, 5.93, 5.66, 5.31, 4.68,3.90, 3.60 and 3.25. The FT-IR spectrum shows bands at 3441, 3215, 1678,1654, 1597, 1476 and 752 cm-1. The solubilities in water and cyclohexaneat 25° C. are 0.16+0.02 and 0.42+0.05 mg/gm respectively. In addition,Form II of finasteride can be prepared by recrystallization from ethylacetate containing between 2 to 30 mg/ml of water and isopropyl acetatecontaining between 2 to 15 mg/ml of water. The isolated solids are driedunder vacuum at about 80° C. and have the same physical characterizationdata as given above. Form II can also be prepared by heating Form I upto about 150° C., holding for about one hour and cooling back to roomtemperature. The Form II prepared in this manner has the same physicalcharacterization data as given above.

EXAMPLE 3

Preparation of Human Prostatic 5α-Reductase.

Samples of human tissue were pulverized using a freezer mill andhomogenized in 40 mM potassium phosphate, pH 6.5, 5 mM magnesiumsulfate, 25 mM potassium chloride, 1 mM phenylmethylsulfonyl fluoride, 1mM dithiothreitol (DTT) containing 0.25 M sucrose using aPotter-Elvehjem homogenizer. A crude nuclear pellet was prepared bycentrifugation of the homogenate at 1,500× g for 15 min. The crudenuclear pellet was washed two times and resuspended in two volumes ofbuffer. Glycerol was added to the resuspended pellet to a finalconcentration of 20%. The enzyme suspension was frozen in aliquots at-80° C. The prostatic reductases were stable for at least 4 months whenstored under these conditions.

5α-Reductase Assay

The reaction mixture for the type 2 5α-reductase contained 40 mM sodiumcitrate, pH 5.5, 0.3 μM [7³ H]-testosterone, 1 mM dithiothreitol and 500μM NADPH in a final volume of 100 μl. Typically, the assay was initiatedby the addition of 50-100 μg prostatic homogenate and incubated at 37°C. After 10-50 min the reaction was quenched by extraction with 250 μlof a mixture of 70% cyclohexane: 30% ethyl acetate containing 10 μg eachDHT and T. The aqueous and organic layers were separated bycentrifugation at 14,000 rpm in an Eppendorf microfuge. The organiclayer was subjected to normal phase HPLC (10 cm Whatman partisil 5silica column equilibrated in 1 ml/min 70% cyclohexane: 30% ethylacetate; retention times: DHT, 6.8-7.2 min; androstanediol, 7.6-8.0 min;T, 9.1-9.7 min). The HPLC system consisted of a Waters Model 680Gradient System equipped with a Hitachi Model 655A autosampler, AppliedBiosystems Model 757 variable UV detector, and a Radiomatic Model A120radioactivity analyzer. The conversion of T to DHT was monitored usingthe radioactivity flow detector by mixing the HPLC effluent with onevolume of Flo Scint 1 (Radiomatic). Under the conditions described, theproduction of DHT was linear for at least 25 min. The only steroidsobserved with the human prostate preparation were T, DHT andandrostanediol.

Inhibition Studies

Compounds were dissolved in 100% ethanol. IC₅₀ values represent theconcentration of inhibitor required to decrease enzyme activity to 50%of the control. IC₅₀ values were determined using a 6 point titrationwhere the concentration of the inhibitor was varied from 0.1 to 1000 nM.

EXAMPLE 4

Macrophotography and Global Photography Procedure for Detection of HairGrowth

A. Macrophotographic Procedure

Location: ID card Haircount target area

Equipment: Film: Kodak-T-max 24 exposure each of same emulsion lotnumber

Camera: Nikon N-6000

Lens: Nikkor 60 mm f2.8

Flashes: Nikon SB-21B Macroflash

Device: registration device

Photographic Procedure

In these clinical photographs, the only variable allowed is thehaircount. Film emulsion, lighting, framing, exposure, and reproductionratios are held constant.

1. The haircount area on the patient is prepared as follows: A small (˜1mm) dot tattoo is placed at the beginning of the study at the leadingedge of the bald area directly anterior to the center of the vertex baldspot, using a commercial tattooing machine or manually (needle and ink).An area approximately one square inch in size, centered at the tattoo atthe leading edge of the balding area, is clipped short (˜2mm). Cut hairsare removed from the area to be photographed, using tape. Compressed airand/or ethanol wipes may also be used to facilitate removal of cuthairs.

2. Magnification: Each lens supplied has a fixed reproduction ratio of1:1.2.

Aperture: Every photograph is taken at f/22.

Film: T-Max 100 (24 exposure) is used.

3. Patient's haircount target area. Three exposures (-2/3, 0, and +2/3f-stop).

A trained technician places a transparency over the photographic printand, using a felt tip pen, places a black dot over each visible hair.The dot map transparency is then counted using image analysis withcomputer assistance.

Photographs are coded with a random number corresponding to study site,visit number and patient allocation number to insure blinding to time.At Month 6, baseline and Month 6 photographs are counted and dataanalyzed for interim analysis. At Month 12, baseline, Month 6 and Month12 photographs are counted and data analyzed for the primary endpoint.

Methodology for detection of hair growth is also described in Olsen, E.A. and DeLong, E., J. American Academy of Dermatology, Vol. 23, p. 470(1990).

B. Global Photographic Procedure

0 Locations: Color card/patient Id Global photograph

Equipment: Film: Kodachrome KR-64 24 exposure each of same emulsion lotnumber

Camera: Nikon N-6000

Lens: Nikkor 60 mm f2.8

Flashes: Nikon SB-23

Photographic Procedure

In these clinical photographs, the only variable allowed is the globalarea's appearance. Anything extraneous to the area (clothing, furniture,walls, etc.) is eliminated from the fields to be photographed.

1. Patients will have global photographs taken prior to hair clippingwith the head in a fixed position (determined by the suppliedstereotactic device). Hair on the patient's head is positionedconsistently so as to not obscure the bald area.

2. Magnification: Each lens supplied has a fixed reproduction

ratio of 1:6.

Aperture: Every photograph will be taken at f/11.

Film: Kodachrome (24 exposure) is used.

3. Patient's global photographs. Three exposures at zero compensation.

Using the above-described methodology, it can be shown thatadministration of 5α-reductase 2 inhibitors, including finasteride, indosages below 5 mg/day per patient, for example, 1 mg/day or 0.2 mg/day,are useful in the treatment of androgenic alopecia, and promote hairgrowth in patients with this condition.

EXAMPLE 5

In another test, finasteride was orally administered for 6 weeks to menwith male pattern baldness at doses of 0.2 mg/day, 1.0 mg/day and 5.0mgs/day. The results of this test showed a significant reduction in DHTcontent in scalp tissue of the test participants.

What is claimed is:
 1. A method of treating female hirsutism comprisingorally administering to a female person in need of such treatment the5α-reductase 2 inhibitor17β-(N-tert-butyl-carbamoyl)-4-aza-5α-androst-1-ene-3-one in a dosageamount of from about 0.01 to 3.0 mg/day.
 2. The method according toclaim 1 wherein the dosage amount is from about 0.05 to 1.0 mg/day. 3.The method according to claim 1 wherein the dosage amount is about 0.2mg/day.
 4. The method according to claim 1 wherein the dosage amount isabout 1.0 mg.